Choroideremia

Summary

Choroideremia (CHM) is an X-linked chorioretinal dystrophy characterized by progressive degeneration of the choroid, retinal pigment epithelium (RPE) and retina.

The prevalence is estimated between 1/50,000-1/100,000.

Affected males experience nyctalopia in the first or second decade of life followed by peripheral visual field constriction with progression from annular scotomas to concentric visual field loss. Impairment in visual acuity is eventually noticed by mid-adulthood. In parallel, fundus changes are observed that consist initially of pigmentary stippling and focal areas of choroid atrophy in the equatorial fundus. In the final stage, there are extensive degenerative changes of the RPE with only remnants of the choroidal vasculature apparent in the macula, far peripheral retina, and near the optic disc. In the advanced stages, the sclera becomes visible on fundus examination in the areas of total choroidal and RPE atrophy. Female carriers generally show no serious visual impairment, but they can show conspicuous fundus abnormalities such as pigment changes in the periphery closely resembling the fine mottling characteristic of the initial stages of the disease in males.

CHM is caused by mutations in the X-linked CHM gene encoding a Ras-related GTPase Rab escort protein (REP)-1. REP-1 is essential for the post-translational activation and subcellular localization of Rab GTP-binding proteins that control vesicle trafficking in secretory and endocytic pathways. Mutations in CHM leads to impaired association of Rab proteins with donor membranes, thus leading to cell death.

The clinical diagnosis is based on the characteristic fundus appearance, defective dark adaptation, peripheral visual field loss, an electroretinogram pattern of rod-cone degeneration, and a family history consistent with X-linked inheritance. CHM genetic diagnosis includes mRNA and DNA CHM gene analysis to detect punctual mutations, deletions involving multiple and single exons, and in rare cases genomic rearrangements.

Differential diagnosis includes retinitis pigmentosa (RP), Usher syndrome type 1, and gyrate atrophy of the choroid and retina (see these terms). X-linked RP is distinguished from CHM by the migration of pigment into the retina. Moreover, choriocapilar and retinal atrophy, leaving areas of bare sclera is only present in CHM. Usher syndrome type 1 is distinguished from CHM by the scalloped areas of significant chorioretinal degeneration that are only typical of CHM. Also, profound deafness and vestibular problems are very rare in CHM cases. Gyrate atrophy is distinguished from CHM by elevated plasma concentration of ornithine.

Carrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if the mutation has been identified in an affected family member.

CHM is inherited in an X-linked manner, with a carrier female having a 50% chance of transmitting the mutation to her offspring.

Management includes periodic ophthalmologic examination to monitor progression of CHM or appearance of cataract, and the use of UV-blocking sunglasses. Treatment is not currently available but a gene therapy trial is ongoing.

The disease has a progressive course that leads to severely reduced visual acuity.

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